The US and Europe are currently experiencing outbreaks of syphilis in men who have sex with men, many of whom are HIV-infected. This is of particular concern because neurosyphilis may be more common in HIV-infected individuals. Our neurosyphilis studies began in 1996. The overall goal of our original proposal was to test the hypothesis that HIV infection impairs clearance of Treponema pallidum from the cerebrospinal fluid (CSF). The results of our studies support this hypothesis. Specifically, individuals with more pronounced HIV-mediated immunosuppression are more likely to have neurosyphilis, and normalization of CSF-Venereal Disease Research Laboratory (VDRL) reactivity after treatment for neurosyphilis is significantly less likely in HIV-infected individuals, particularly those with advanced immunosuppression. In our competing renewal, we focused on predicting neurosyphilis and its treatment response. In the last 15 months, we have made substantial progress in addressing our previous Aims. We have shown that the CSF cellular phenotype can be used to support a diagnosis of neurosyphilis in HIV-infected patients, have additional preliminary data in support of the association between greater genetic diversity of blood T. pallidum and neurosyphilis, and have identified new markers of neurosyphilis treatment response. As of Dec 1,2003, we have enrolled and obtained CSF from 470 subjects with syphilis, and 91 have had at least one follow-up lumbar puncture after neurosyphilis treatment. Approximately three-quarters of our subjects are also HIV-infected. In this competing renewal application, we continue to focus on clinically and pathogenetically important questions regarding neurosyphilis and HIV. The Specific Aims are: 1) Identify measures that predict a high likelihood of neurosyphilis in HIV-infected and -uninfected individuals; 2) Distinguish CSF pleocytosis due to T. pallidum infection from CSF pleocytosis due to HIV infection; 3) Determine factors associated with response to neurosyphilis therapy in HIV-infected and -uninfected individuals. Our ongoing study is the largest investigation of neurosyphilis in many decades, and is the only study with sufficient power to address the effect of concomitant HIV infection on development of neurosyphilis and the response to neurosyphilis therapy in both HIV-infected and -uninfected individuals. [unreadable] [unreadable]